The objective of the research proposal is to explore the use of carriers for a specific drug, methotrexate, to improve its therapeutic index in three specific areas: 1) To determine whether modification of the pharmacokinetics of MTX by coupling it to high M.W. carriers can be used to achieve increased steady-state concentration ratios of MTX in pleural and peritoneal cavities relative to blood. If the drug-carrier is injected into these cavities and if tumor cells confined to these cavities can be exposed to very high concentrations of MTX for prolonged periods of time while exposing the systemic circulation to only low levels of MTX, then toxicity in normal tissues can be readily controlled with small amounts of systemically administered leucovorin. 2) To determine whether the different transport properties of MTX linked to high M.W. carriers can be used to overcome the resistance of MTX-transport deficient cells in vivo. 3) a. To study the relative uptake rates of selected proteins and normal human plasma proteins either alone or conjugated to MTX into human bone marrow cells and several human tumor lines in tissue culture. b. To assess the in vivo selectivity and effectiveness of the MTX carrier complexes found to have the greatest differential uptake in vitro, using nude mice carrying the same human tumor lines.